Figure 12.3. Schematic diagram of MLV-based vectors. The vectors used in these studies are presented in linear form. The parental LXSH vector includes the 5' M-MCV LTR, the psi packaging site and the 5' ga region, the hygromycin resistance gene under the control of the SV40 promoter, and the 3' LTR of M-MLV Vectors are modified by insertion of either GD-17 U3 and/or LacZ. (Copyright, Ann. NY Acad. Sci., 998:2003).
/#2 inflam #4 nAChRifc-react/ve 4 CD4+ T ce||s resspjond - #3 increased to locally encountered retUm of/
. #1 peripheral nAChRa-reactive CD4+ T cells escape central deletion
Figure 12.4. A new hypothesis bearing on the intrathymic pathogenesis of myasthenia gravis (MG). The hypothesis (see text for details) describes events leading to the activation of peripheral AChRa-specific CD4+ T following their entry into the thymic medulla. (Copyright. Ann. NY Acad. Sci., 998:2003).
the entry of peripheral T cells into the thymus, P-gal-immunized mice were injected i.v. with a population of CFSE-labeled CD4+ T cells specific for an unrelated antigen 4 days after i.t. injection of LBSHG or LXSHG. The CD4+ T cells were derived from a transgenic mouse bearing a T cell receptor that recognized an influenza hemagglutinin peptide (provided by Dr. Andrew Caton, Wistar Institute, Philadelphia,Pennsylvania). Animals that received LBSHG had 4.2-fold more CFSE-labeled CD4+ thymic immigrants than animals that received the control vector.
This model provides us with an opportunity to test a new hypothesis bearing on the intrathymic pathogenesis of MG (Figure 12.4). The hypothesis states that an inflammatory reaction to an unrelated antigen within the medulla of the
Table 12.1. Rationale for Intrathymic Pathogenesis Hypothesis nAChRa-reactive CD4+ T cells can be found in the blood of healthy donors as well as MG patients nAChRa-reactive T and B cells are recovered from MG thymus but not "control" thymus nAChRa is constitutively expressed on thymic myoid cells and thymic epithelial cells nAChRa mRNA and MHC class II protein expression on human thymic epithelial cells is upregulated by interferon-y Peripheral T cells traffic to thymus where they enter the medulla thymus promotes the entry of peripheral AChRa-reactive CD4+ T cells that had escaped central deletion. These cells enter the thymus in the medullary compartment where they encounter AChRa peptides expressed by APCs. The concomitant intrathymic inflammatory reaction creates a milieu that favors activation of these autoreactive T cells, i.e., upregulation of MHC class II antigens and cos-timulatory molecules on APCs, and perhaps upregulation of AChR expression on TECs. In this scenario, AChR-expressing thymic medullary epithelial cells in addition to local professional APCs might serve as the agents of T cell priming. Presentation of AChRa epitopes to the CD4+ thymic immigrants would lead to their activation, help for locally stimulated aAChR-reactive B cells, the production of anti-AChR antibodies, and GCs, and the development of MG. The rationale for this hypothesis is outlined in Table 12.1.
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